RESUMO
Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine the role of NRP-1 in pancreatic cancer, NRP-1 was stably transfected into the human pancreatic cancer cell line FG. Signal transduction was assessed by Western blot analysis. Susceptibility to anoikis (detachment induced apoptosis) was evaluated by colony formation after growth in suspension. Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1. Differential expression of apoptosis-related genes was determined by gene array and further evaluated by Western blot analysis. Neuropilin-1 overexpression increased constitutive mitogen activated protein kinase (MAPK) signalling, possibly via an autocrine loop. Neuropilin-1 overexpression in FG cells enhanced anoikis resistance and increased survival of cells by > 30% after exposure to clinically relevant levels of gemcitabine and 5-FU. In contrast, downregulation of NRP-1 expression in Panc-1 cells markedly increased chemosensitivity, inducing > 50% more cell death at clinically relevant concentrations of gemcitabine. Neuropilin-1 overexpression also increased expression of the antiapoptotic regulator, MCL-1. Neuropilin-1 overexpression in pancreatic cancer cell lines is associated with (a) increased constitutive MAPK signalling, (b) inhibition of anoikis, and (c) chemoresistance. Targeting NRP-1 in pancreatic cancer cells may downregulate survival signalling pathways and increase sensitivity to chemotherapy.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Fluoruracila/farmacologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Neuropilina-1/biossíntese , Neuropilina-1/fisiologia , Neoplasias Pancreáticas/patologia , Apoptose , Western Blotting , Resistencia a Medicamentos Antineoplásicos , Perfilação da Expressão Gênica , Humanos , Fenótipo , Transdução de Sinais , Transfecção , Células Tumorais Cultivadas , Regulação para Cima , GencitabinaRESUMO
Two decades ago, Crary reported his anecdotal observation that a supplemental antioxidant regimen including high-dose selenium (500 mcg daily) appeared to slow the progression of visual loss in diabetic retinopathy and macular degeneration. Recently, selenium has been shown to down-regulate VEGF production by rodent cancer cells, both in vivo and in vitro; this effect is dose-dependent and, like the anticarcinogenic activity of selenium, is mediated by methyselenol. If increased selenium exposure can likewise suppress VEGF production in the hypoxic retina, a straightforward explanation for Crary's observation may be at hand. Since selenium is inexpensive and non-toxic in the dose employed by Crary, an effort to replicate his findings is warranted.
Assuntos
Hipóxia Celular/efeitos dos fármacos , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Suplementos Nutricionais , Modelos Biológicos , Retina/metabolismo , Selênio/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/metabolismo , Administração Oral , Animais , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Humanos , Retina/efeitos dos fármacos , Resultado do TratamentoRESUMO
Eph receptor tyrosine kinases (RTKs) and their membrane-bound ligands, the ephrins, are essential for embryonic vascular development. Recently, it has been demonstrated that overexpression of specific Ephs and ephrins is associated with a poor prognosis in human tumours. Our group has shown that EphB and the ephrin-B subfamilies are coexpressed in human colorectal cancer, and ephrin-B2 is expressed at higher levels in human colorectal cancer than in adjacent normal mucosa. As the Eph/ephrin system is involved in embryologic vasculogenesis and ephrin-B2 is expressed ubiquitously in all colon cancers studied in our laboratory, we hypothesised that overexpression of ephrin-B2 in colon cancer cells may induce tumour angiogenesis and increase tumour growth. To investigate this hypothesis, we stably transfected KM12L4 human colon cancer cells with ephrin-B2 to study its effect on tumour growth in vivo. We found that overexpression of ephrin-B2 markedly decreased tumour growth in a mouse xenograft model. Immunohistochemical staining showed that ephrin-B2 transfectants produced higher tumour microvessel density and lower tumour cell proliferation than did parental or vector-transfected control cells. Using (51)Cr-labelled red blood cells (RBCs) to determine the functional blood volume in tumours, we demonstrated that tumours from ephrin-B2-transfected cells had significantly decreased blood volume compared with tumours from parental or vector-transfected control cells. Evaluation of in vitro parameters of cell cycle mediators demonstrated no alteration in the cell cycle. Although ephrin-B2 transfection increased tumour vessel density, the decrease in blood perfusion suggests that these vessels may be 'dysfunctional'. We conclude that overexpression of ephrin-B2 suppresses tumour cell growth and vascular function in this in vivo colon cancer model.
Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Efrina-B2/biossíntese , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica , Animais , Northern Blotting , Ciclo Celular , Divisão Celular , Efrina-B2/análise , Humanos , Imuno-Histoquímica , Ligantes , Camundongos , Camundongos Nus , Neoplasias Experimentais , Proteínas Tirosina Quinases/farmacologia , Transfecção , Células Tumorais CultivadasRESUMO
The purpose of this study was to examine the effects of ZD6126, a novel vascular-targeting agent, on tumour growth and angiogenesis in an orthotopic model of gastric cancer. TMK-1 human gastric adenocarcinoma cells were injected into the gastric wall of nude mice. After the tumours were established (day 14), therapy was initiated. Mice (n=11-12/group) received (a). vehicle, (b). ZD6126 at 100 mg x kg day(-1) i.p. one time per week or (c) ZD6126 at 100 mg x kg day(-1) i.p. five times per week. Tumour mass, volume and the presence or absence of peritoneal carcinomatosis were determined at sacrifice on day 38. Tumours from each group were stained for markers of blood vessels, proliferation and apoptosis. To further define the time frame of the vascular-targeting effects of chronic therapy with ZD6126, TMK-1 cells were again injected into the gastric wall of mice in a second experiment. On day 14, a single i.p. injection of ZD6126 100 mg x kg(-1) mouse(-1) or vehicle was delivered. Groups of three mice each were killed and the tumours harvested at days 1, 3 and 5 post-ZD6126 injection. Tumours were processed and stained for endothelial and tumour cell apoptosis and proliferation. No overt toxicity was observed with ZD6126 therapy. ZD6126 led to a marked inhibition of tumour growth (82% decrease vs control (P<0.001)). ZD6126 also led to a significant decrease in the incidence of peritoneal carcinomatosis (10 out of 12 controls, vs one out of 12 ZD6126) (P<0.01). Histological analysis of tumours revealed large regions of central necrosis in the treated group, as well as a dramatic increase in tumour cell apoptosis (7.4-fold increase (P<0.001)), consistent with the vascular-targeting activity of ZD6126. Mice treated with ZD6126 demonstrated a 59% decrease in PCNA-positive cells (P< 0.02), indicating reduced tumour cell proliferation. In addition, tumours treated with ZD6126 exhibited a 40% decrease in microvessel density (P<0.05). Results from mice treated with a single injection of ZD6126 demonstrated the acute effects this agent has on the tumour vasculature. The ratio of endothelial cell apoptosis to endothelial cell proliferation was increased within 24 h of a single injection. In conclusion, ZD6126 significantly inhibited tumour growth and metastasis in an orthotopic model of human gastric adenocarcinoma, without detectable problematic adverse effects. These data suggest that ZD6126 may be worthy of investigation in the treatment of primary gastric adenocarcinoma.
Assuntos
Adenocarcinoma/patologia , Metástase Neoplásica/fisiopatologia , Neovascularização Patológica , Compostos Organofosforados/farmacologia , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/fisiopatologia , Animais , Apoptose , Divisão Celular , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais , Humanos , Camundongos , Camundongos Nus , Células Tumorais CultivadasRESUMO
A new category of anti-anginal drug - exemplified by ranolazine - is believed to work by partially inhibiting cardiac oxidation of fatty acids; oxidation of glucose requires less oxygen per mol of ATP generated, and thus is preferable to fat oxidation when oxygen availability is limiting in underperfused cardiac tissue. Unfortunately, there is no reason to believe that these drugs inhibit fat oxidation selectively in the heart; thus, chronic use of these drugs can be expected to increase body fat stores until the original rate of fat oxidation is restored by mass action - presumably negating the therapeutic benefit in angina, while exacerbating the manifold adverse effects of insulin resistance syndrome. The rational way to decrease cardiac metabolic reliance on fatty acids is to consume a very-low-fat quasi-vegan diet (i.e., 10% fat calories). Indeed, such diets are known to have a rapid and substantial therapeutic impact on anginal symptoms, while concurrently benefiting insulin sensitivity, markedly improving serum lipid profile, promoting leanness, and lessening coronary risk. A reduction in diurnal insulin secretion might also be achieved, which would be expected to decrease sympathetic activity. While reduced myocardial demand for oxygen doubtless contributes to the beneficial impact of such diets on angina, it is likely that improved cardiac perfusion consequent to improved endothelium-dependent vasodilation also plays a role in this regard. Supplemental carnitine, also beneficial in angina, appears to improve utilization of glucose in the ischemic myocardium by lowering elevated acetyl-coA levels and thereby disinhibiting pyruvate dehydrogenase. Certain other nutraceuticals may aid control of angina by improving endothelial function. In the longer term, these measures have the potential to slow or reverse the progression of stenotic lesions that underlie most cases of angina. These safe and relatively inexpensive nutritional strategies for coping with angina deserve far more attention than orthodox medical practice has thus far accorded them.
Assuntos
Angina Pectoris/prevenção & controle , Angina Pectoris/fisiopatologia , Dieta com Restrição de Gorduras/métodos , Dieta Vegetariana , Endotélio Vascular/fisiopatologia , Ácidos Graxos/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Acetanilidas , Carnitina/uso terapêutico , Quimioterapia Adjuvante/métodos , Inibidores Enzimáticos/uso terapêutico , Coração/inervação , Coração/fisiopatologia , Humanos , Piperazinas/uso terapêutico , RanolazinaRESUMO
Although exposure to ultraviolet light is often viewed as pathogenic owing to its role in the genesis of skin cancer and skin aging, there is growing epidemiological evidence that such exposure may decrease risk for a number of more serious cancers, may have a favorable impact on blood pressure and vascular health, and may help to prevent certain autoimmune disorders - in addition to its well-known influence on bone density. Most likely, these health benefits are reflective of improved vitamin D status. Increased synthesis or intake of vitamin D can be expected to down-regulate parathyroid hormone (PTH), and to increase autocrine synthesis of its active metabolite calcitriol in certain tissues; these effects, in turn, may impact cancer risk, vascular health, immune regulation, and bone density through a variety of mechanisms. Presumably, a truly adequate supplemental intake of vitamin D - manyfold higher than the grossly inadequate current RDA - could replicate the benefits of optimal UV exposure, without however damaging the skin. Diets moderately low in bioavailable phosphate - like many vegan diets - might be expected to have a complementary impact on disease risks, inasmuch as serum phosphate suppresses renal calcitriol synthesis while up-regulating that of PTH. A proviso is that the impact of dietary phosphorus on bone health is more equivocal than that of vitamin D. Increased intakes of calcium, on the other hand, down-regulate the production of both PTH and calcitriol - the latter effect may explain why the impact of dietary calcium on cancer risk (excepting colon cancer), hypertension, and autoimmunity is not clearly positive. An overview suggests that a vegan diet supplemented with high-dose vitamin D should increase both systemic and autocrine calcitriol production while suppressing PTH secretion, and thus should represent a highly effective way to achieve the wide-ranging health protection conferred by optimal UV exposure.
Assuntos
Dieta Vegetariana , Fosfatos/fisiologia , Raios Ultravioleta , Autoimunidade , Calcitriol/metabolismo , Cálcio/metabolismo , Cálcio da Dieta , Regulação para Baixo , Humanos , Luz , Modelos Teóricos , Hormônio Paratireóideo/biossíntese , Hormônio Paratireóideo/metabolismo , Fósforo/metabolismo , Fósforo na Dieta , Risco , Vitamina D/metabolismo , Vitamina D/fisiologiaRESUMO
In HIV patients, chronic treatment with protease inhibitors often precipitates a peripheral lipodystrophy associated with insulin resistance syndrome and premature coronary disease. In vitro studies demonstrate that these drugs can compromise the ability of adipocytes to store triglycerides; in vivo, peripheral subcutaneous adipocytes appear to be most affected, such that body fat often redistributes to visceral or truncal adipose stores. Dysfunction of peripheral subcutaneous adipocytes - ordinarily quite efficient for storing fat - can be expected to give rise to an excessive flux of free fatty acids (FFAs) following fatty meals; chronic overexposure of tissues to FFAs is a likely explanation for the insulin resistance syndrome associated with lipodystrophy. These considerations suggest that a very-low-fat diet - less than 15% fat calories - may ameliorate the cardiovascular risk associated with lipodystrophy; such diets are known to have a favorable effect on the insulin sensitivity of healthy subjects. Very-low-fat whole-food vegan diets are particularly recommendable in this context, as they may help to shrink visceral fat depots while markedly reducing LDL cholesterol. Appropriate adjunctive measures may include aerobic exercise training - beneficial both for insulin sensitivity and weight control - as well as administration of statins or policosanol, and of fibrates or fish oil, to decrease LDL and triglycerides, respectively. Despite perceptions to the contrary, very-low-fat diets can meet with good compliance in well-motivated subjects given appropriate instruction.
Assuntos
Dieta com Restrição de Gorduras , Infecções por HIV/complicações , Doença Iatrogênica , Lipodistrofia/etiologia , Adipócitos/metabolismo , LDL-Colesterol/metabolismo , Dieta Vegetariana , Humanos , Resistência à Insulina , Modelos Teóricos , Período Pós-Prandial , Inibidores de Proteases/farmacologiaRESUMO
There is growing evidence that increases in both hematocrit and body iron stores are components of the insulin resistance syndrome. The ability of insulin and of IGF-I - whose effective activity is increased in the context of insulin resistance - to boost activity of the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), may be at least partially responsible for this association. HIF-1alpha, which functions physiologically as a detector of both hypoxia and iron-deficiency, promotes synthesis of erythropoietin, and may also mediate the up-regulatory impact of hypoxia on intestinal iron absorption. Insulin/IGF-I may also influence erythropoiesis more directly, as they are growth factors for developing reticulocytes. Conversely, the activation of HIF-1alpha associated with iron deficiency may be responsible for the increased glucose tolerance noted in iron-deficient animals; HIF-1alpha promotes efficient glucose uptake and glycolysis - a sensible adaptation to hypoxia - by inducing increased synthesis of glucose transporters and glycolytic enzymes. Recent reports that phlebotomy can increase the efficiency of muscle glucose uptake in lean healthy omnivores are intriguing and require further confirmation. Whether increased iron stores contribute to the elevated vascular risk associated with insulin resistance is doubtful, inasmuch as most prospective studies fail to correlate serum ferritin or transferrin saturation with subsequent vascular events. However, current data are reasonably consistent with the possibility that moderately elevated iron stores are associated with increased overall risk for cancer - and for colorectal cancer in particular; free iron may play a catalytic role in 'spontaneous' mutagenesis. Thus, iron excess may mediate at least some of the increased cancer risk associated with insulin resistance and heme-rich diets. People who are insulin resistant can minimize any health risk associated with iron overload by avoiding heme-rich flesh foods and donating blood regularly.
Assuntos
Hematócrito , Hiperinsulinismo , Ferro/farmacocinética , Fatores de Transcrição/biossíntese , Regulação para Cima , Eritropoese , Glucose/metabolismo , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Insulina/metabolismo , Resistência à Insulina , Ferro/metabolismo , Modelos Teóricos , Músculos/metabolismo , Estudos Prospectivos , Reticulócitos/metabolismoRESUMO
Increased free intracellular calcium ([Ca(2+)](i)) in adipocytes blunts the lipolytic response to catecholamines by activating phosphodiesterase 3B - the same enzyme that mediates the antilipolytic effect of insulin - while also compromising the efficiency of insulin-stimulated glucose uptake. Physiological increases in parathyroid hormone (PTH) have been shown to increase [Ca(2+)](i) in adipocytes. These considerations may rationalize recent evidence that high dietary intakes of calcium and/or dairy products may reduce risk for obesity, diabetes, and insulin-resistance syndrome, and they predict that other dietary measures which down-regulate PTH - such as good vitamin D status, and moderation in phosphate and salt intakes - may likewise be beneficial in these respects. Consistent with this position are reports that body weight is elevated in elderly subjects with both primary and secondary hyperparathyroidism; furthermore, insulin resistance is a well-known complication of both forms of hyperparathyroidism. The fact that regular alcohol consumption is associated with decreased PTH secretion may help to explain why moderate drinkers are less prone to insulin resistance, diabetes, and - in women - obesity. Down-regulation of PTH cannot be expected to promote dramatic weight loss, but in the long-term it may lessen risk for significant weight gain and diabetes, and conceivably may potentiate the fat loss achievable with caloric restriction and/or exercise.
Assuntos
Consumo de Bebidas Alcoólicas , Peso Corporal/efeitos dos fármacos , Cálcio/metabolismo , Catecolaminas/antagonistas & inibidores , Hormônio Paratireóideo/fisiologia , Vitamina D/metabolismo , Aumento de Peso , Adipócitos/metabolismo , Calcitriol/fisiologia , Regulação para Baixo , Feminino , Humanos , Lipólise , Masculino , Modelos Teóricos , Obesidade/etiologia , Hormônio Paratireóideo/biossínteseRESUMO
There is recent evidence that nitric oxide blocks IL-6 signaling in hepatocytes by inhibiting activation of Stat3. If this effect is mediated by cGMP, then high-dose biotin--which can directly activate guanylyl cyclase--may have the potential to suppress hepatic production of acute phase proteins.
Assuntos
Reação de Fase Aguda , Biotina/farmacologia , Regulação para Baixo , Óxido Nítrico/metabolismo , Animais , Biotina/metabolismo , Células Cultivadas , GMP Cíclico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Inflamação , Interleucina-6/antagonistas & inibidores , Fígado/enzimologia , Modelos Teóricos , Ratos , Fator de Transcrição STAT3 , Transdução de Sinais , Transativadores/metabolismoRESUMO
A common polymorphism of the 54th codon of fatty acid-binding protein 2 (FABP2), in which threonine substitutes for alanine (T54), has been linked to insulin resistance and/or increased postprandial triglycerides in various studies. I propose that, in subjects expressing T54, the secretion of gastric inhibitory polypeptide (GIP) evoked by fatty meals is subnormal, such that adipocytes are less efficient in converting chylomicrons to stored triglyceride. The increased postprandial free fatty acid flux which this may imply could be expected to exacerbate insulin resistance syndrome--thus accounting for the association of T54 with insulin resistance in epidemiological studies. If this thesis proves to be correct, it will help to clarify the importance of appropriate GIP secretion to maintenance of insulin sensitivity in the context of fatty diets.
Assuntos
Proteínas de Transporte/genética , Gorduras na Dieta , Polipeptídeo Inibidor Gástrico/metabolismo , Insulina/metabolismo , Polimorfismo Genético , Proteínas Supressoras de Tumor , Alanina/química , Alelos , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Humanos , Modelos Teóricos , Triglicerídeos/químicaRESUMO
During angiostatic therapy, tumor hypoxia will activate the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), and will select for mutations which up-regulate the activity of this factor. This adaptation will increase tumor angiogenic capacity, while aiding the survival of poorly nourished cancer cells. A further effect of HIF-1alpha is to increase expression of transferrin receptors. The natural antimalarial drug artemisinin is selectively toxic to iron-loaded cells (such as malarial parasites), and it has recently been suggested that, inasmuch as many cancers overexpress transferrin receptors, such cancers might be treatable with a regimen comprised of iron supplementation and high-dose artemisinin. Thus, it can be anticipated that many tumors which evolve relative resistance to angiostatic therapy will be selectively susceptible to attack by the iron-loading/artemisinin strategy.
Assuntos
Inibidores da Angiogênese/farmacologia , Fatores de Transcrição/metabolismo , Artemisininas/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Ferro/metabolismo , Modelos Teóricos , Mutação , Oxigênio/metabolismo , Receptores da Transferrina/metabolismo , Sesquiterpenos/farmacologia , Regulação para CimaRESUMO
IGF-I acts on vascular endothelium to activate nitric oxide synthase, thereby promoting vascular health; there is reason to believe that this protection is especially crucial to the cerebral vasculature, helping to ward off thrombotic strokes. IGF-I may also promote the structural integrity of cerebral arteries, thereby offering protection from hemorrhagic stroke. These considerations may help to explain why tallness is associated with low stroke risk, whereas growth hormone deficiency increases stroke risk--and why age-adjusted stroke mortality has been exceptionally high in rural Asians eating quasi-vegan diets, but has been declining steadily in Asia as diets have become progressively higher in animal products. There is good reason to suspect that low-fat vegan diets tend to down-regulate systemic IGF-I activity; this effect would be expected to increase stroke risk in vegans. Furthermore, epidemiology suggests that low serum cholesterol, and possibly also a low dietary intake of saturated fat--both characteristic of those adopting low-fat vegan diets--may also increase stroke risk. Vegans are thus well advised to adopt practical countermeasures to minimize stroke risk--the most definitive of which may be salt restriction. A high potassium intake, aerobic exercise training, whole grains, moderate alcohol consumption, low-dose aspirin, statin or policosanol therapy, green tea, and supplementation with fish oil, taurine, arginine, and B vitamins--as well as pharmacotherapy of hypertension if warranted--are other practical measures for lowering stroke risk. Although low-fat vegan diets may markedly reduce risk for coronary disease, diabetes, and many common types of cancer, an increased risk for stroke may represent an 'Achilles heel'. Nonetheless, vegans have the potential to achieve a truly exceptional 'healthspan' if they face this problem forthrightly by restricting salt intake and taking other practical measures that promote cerebrovascular health.
Assuntos
Dieta Vegetariana/efeitos adversos , Fator de Crescimento Insulin-Like I/metabolismo , Acidente Vascular Cerebral/prevenção & controle , Animais , Humanos , Fatores de RiscoRESUMO
The aim of this study was to determine whether epidermal hyperplasia overlying cutaneous human melanoma is associated with increased tumour angiogenesis, tumour growth and the potential for metastasis. Forty-two surgical specimens of cutaneous human melanoma of different depths, each containing epidermis present in the tumour-free margin, were analysed by immunohistochemistry for the expression of the pro-angiogenic molecules basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) and the anti-angiogenic molecule interferon-beta (IFN-beta). The epidermis overlying intermediate and thick (1.0-10.0 mm), but not thin (0.5-1.0 mm), melanoma specimens was hyperplastic. Although the expression level of bFGF, VEGF and IL-8 in the epidermis directly overlying the tumour was similar to that in the distant epidermis, the expression of IFN-beta was significantly decreased in keratinocytes overlying intermediate and thick, but not thin, melanomas. The microvessel density was also increased in intermediate and thick specimens. Human melanoma cells were injected subcutaneously into nude mice. The resulting tumours were used to determine the association between overlying epidermal hyperplasia and neoplastic angiogenesis. Similar to human autochthonous melanomas, epidermal hyperplasia was found only over lesions produced by metastatic cells. Although there was no change in the expression of the pro-angiogenic molecules, the expression of IFN-beta was significantly decreased in the hyperplastic epidermis. Conditioned medium collected from cultures of the metastatic cell line induced in vitro proliferation of mouse keratinocytes, whereas conditioned medium collected from cultures of the non-metastatic cell line did not. Collectively, the data demonstrate that metastatic melanoma cells induce keratinocyte proliferation, leading to decreased expression of the negative regulator of angiogenesis, IFN-beta, and hence to increased angiogenesis.
Assuntos
Epiderme/patologia , Melanoma/irrigação sanguínea , Melanoma/patologia , Neovascularização Patológica/patologia , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/patologia , Animais , Epiderme/metabolismo , Substâncias de Crescimento/metabolismo , Humanos , Hiperplasia , Imuno-Histoquímica , Interferon beta/metabolismo , Masculino , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/metabolismo , Neoplasias Cutâneas/metabolismoRESUMO
Insulin resistance syndrome is associated with endothelial dysfunction characterized by decreased nitric oxide bioactivity and subnormal endothelium-dependent vasodilation. Excessive exposure to free fatty acids (FFAs) is thought to mediate this dysfunction, at least in part, since free fatty acid overexposure, both in vivo and in vitro, decreases the capacity of endothelial cells to generate bioactive nitric oxide. Yet this endothelial dysfunction tends to correlate, not with fasting FFA levels, but with poor insulin suppressibility of FFA flux postprandially. I propose that triglycerides are synthesized and stored in endothelial cells during the postprandial period, when FFAs and insulin are jointly elevated, and that this triglyceride pool serves as a source of FFA overexposure postabsorptively--thus accounting for the endothelial dysfunction associated with insulin resistance syndrome and the role of excessive postprandial FFA flux in its induction. Since a substantial proportion of postprandial FFA flux derives, not from adipocytes, but from the fat provided by meals, these considerations may help to rationalize the documented clinical utility of very-low-fat diets for management of coronary disease.
Assuntos
Gorduras na Dieta/efeitos adversos , Endotélio Vascular/metabolismo , Resistência à Insulina/fisiologia , Triglicerídeos/metabolismo , Dieta com Restrição de Gorduras/efeitos adversos , Dieta Vegetariana , Ácidos Graxos não Esterificados/sangue , Humanos , Modelos Biológicos , Período Pós-Prandial/fisiologiaRESUMO
A great deal of effort is now being devoted to the development of new drugs that hopefully will control the spread of inoperable cancer by safely inhibiting tumor-evoked angiogenesis. However, there is growing evidence that certain practical nutritional measures have the potential to slow tumor angiogenesis, and it is reasonable to anticipate that, by combining several measures that work in distinct but complementary ways to impede the angiogenic process, a clinically useful 'multifocal angiostatic therapy' (MAT) might be devised. Several measures which might reasonably be included in such a protocol are discussed below, and include: a low-fat, low-glycemic index vegan diet, which may down-regulate the systemic IGF-I activity that supports angiogenesis; supplemental omega-3-rich fish oil, which has been shown to inhibit endothelial expression of Flk-1, a functionally crucial receptor for VEGF, and also can suppress tumor production of pro-angiogenic eicosanoids; high-dose selenium, which has recently been shown to inhibit tumor production of VEGF; green tea polyphenols, which can suppress endothelial responsiveness to both VEGF and fibroblast growth factor; and high-dose glycine, whose recently reported angiostatic activity may reflect inhibition of endothelial cell mitosis, possibly mediated by activation of glycine-gated chloride channels. In light of evidence that tumor-evoked angiogenesis has a high requirement for copper, copper depletion may have exceptional potential as an angiostatic measure, and is most efficiently achieved with the copper-chelating drug tetrathiomolybdate. If logistical difficulties make it difficult to acquire this experimental drug, high-dose zinc supplementation can achieve a slower depletion of the body's copper pool, and in any case can be used as maintenance therapy to maintain an adequate level of copper depletion. A provisional protocol is offered for a nutritionally based MAT entailing a vegan diet and supplemental intakes of fish oil, selenium, green tea polyphenols, glycine, and zinc. Inasmuch as cox-2 is overexpressed in many cancers, and cAMP can boost tumor production of various angiogenic factors as well as autogenous growth factors, adjunctive use of cox-2-specific NSAIDS may be warranted in some cases.
Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias/terapia , Neovascularização Patológica , Fenômenos Fisiológicos da Nutrição , Indutores da Angiogênese , Animais , Cobre/metabolismo , AMP Cíclico/metabolismo , Dieta , Dieta Vegetariana , Regulação para Baixo , Exercício Físico , Ácidos Graxos Ômega-3/metabolismo , Flavonoides , Glicina/metabolismo , Glicina/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/biossíntese , Neoplasias/patologia , Neoplasias/prevenção & controle , Fenóis , Polifenóis , Selênio/uso terapêutico , Chá , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossínteseRESUMO
Although a salted diet appears to be a sine qua non for the development of essential hypertension, low-salt diets often have a modest or even negligible impact on the blood pressure of hypertensives; this suggests that salt, perhaps often acting in concert with other aspects of a modern, rich diet, may set in place certain metabolic vicious cycles that sustain blood pressure elevation even when dietary salt is eliminated. Therapeutic fasting is known to lower elevated blood pressure - presumably in large part because it minimizes insulin secretion - and may have the potential to break some of these vicious cycles. Goldhamer has recently reported that a regimen comprised of a water-only fast of moderate duration, followed by a transition to a low-fat, low-salt, whole-food vegan diet, achieves dramatic reductions in the blood pressure of hypertensives, such that the large majority of patients can be restored to normotensive status, in the absence of any drug therapy. Although long-term follow-up of these subjects has been sporadic, the available data suggest that these large reductions is blood pressure can be conserved in patients who remain compliant with the follow-up diet - in other words, a 'cure' for hypertension may be feasible. If a protein-sparing modified fast can be shown to be virtually as effective as a total fast for achieving these benefits, it may be possible to implement this regimen safely on an outpatient basis. The ability of therapeutic fasts to break metabolic vicious cycles may also contribute to the efficacy of fasting in the treatment of type 2 diabetes and autoimmune disorders. As a general principle, if a metabolic disorder is susceptible to prevention - but not reversal - by a specific diet, and therapeutic fasting has a temporary favorable impact on this disorder, then a more definitive therapy may consist of a therapeutic fast, followed up by the protective diet as a maintenance regimen.
Assuntos
Dieta Vegetariana , Gorduras na Dieta/administração & dosagem , Jejum , Hipertensão/dietoterapia , Cloreto de Sódio na Dieta/administração & dosagem , Humanos , Hipertensão/metabolismoRESUMO
The findings of the recent HOPE trial strongly suggest that ACE inhibitor therapy may reduce risk for type 2 diabetes in patients who are non-diabetic at baseline. This finding is readily rationalized by previous evidence that bradykinin, acting via B2 receptors, can potentiate the insulin responsiveness of both adipocytes and muscle fibers; this effect may be mediated by a reduction in the activity of a tyrosine phosphatase that targets the insulin receptor. ACE inhibitors, in turn, increase the availability of bradykinin by suppressing its proteolytic degradation. In light of the fact that the development of insulin resistance in adipocytes is responsible for the excessive free fatty acid flux that gives rise to the diabetic syndrome, a favorable impact of ACE inhibition on adipocyte insulin responsiveness - complemented by a potentiation of the direct action of bradykinin on skeletal muscle - offers a satisfying explanation for the prevention of diabetes observed during ACE inhibitor therapy. Since the population at risk for diabetes is huge and increasing dramatically, the recent development of orally absorbable food-derived peptides with clinically significant ACE inhibitory activity - such as 'Katsuobushi oligopeptides' derived from bonito - may make it more logistically feasible to achieve this protection on a widescale basis, while simultaneously promoting blood pressure control and reducing risk for atherothrombotic disease.
Assuntos
Adipócitos/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bradicinina/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Idoso , Bradicinina/efeitos dos fármacos , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/prevenção & controle , Suscetibilidade a Doenças/terapia , Humanos , Insulina/metabolismo , Resistência à Insulina , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Medição de RiscoRESUMO
The epidermal growth factor receptor (EGF-R) pathway plays a pivotal role in the progression of human gastric cancer. The angiogenic factor vascular endothelial growth factor (VEGF) has been shown to be induced by EGF in various cancer cell lines. Neuropilin-1 (NRP-1) acts as a coreceptor for VEGF-165 and increases its affinity for VEGF receptor 2 (VEGFR-2) in endothelial cells. Furthermore, NRP-1 has been found to be expressed by tumour cells and has been shown to enhance tumour angiogenesis and growth in preclinical models. We examined the expression of NRP-1 mRNA and EGF-R protein in seven human gastric cancer cell lines. NRP-1 expression was expressed in five of seven cell lines, and EGF-R expression closely mirrored NRP-1 expression. Moreover, in EGF-R-positive NCI-N87 and ST-2 cells, EGF induced both NRP-1 and VEGF mRNA expression. C225, a monoclonal antibody to EGF-R, blocked EGF-induced NRP-1 and VEGF expression in NCI-N87 cells in a dose-dependent manner. The treatment of NCI-N87 cells with EGF resulted in increases in phosphorylation of Erk1/2, Akt, and P38. Blockade of the Erk, phosphatidylinositol-3 kinase/Akt, or P38 pathways in this cell line prevented EGF induction of NRP-1 and VEGF. These results suggest that regulation of NRP-1 expression in human gastric cancer is intimately associated with the EGF/EGF-R system. Activation of EGF-R might contribute to gastric cancer angiogenesis by a mechanism that involves upregulation of VEGF and NRP-1 expression via multiple signalling pathways.